Hot flashes are the most common symptoms experienced by women who are perimenopausal or postmenopausal and are also found in men with prostate cancer who undergo androgen deprivation therapy (ADT). Hot flashes are generally systemic and likely result from an alteration in the thermoregulatory set-point center, which is located in the pre-optic anterior hypothalamus, with involvement of dopamine, serotonin, norepinephrine, and their respective receptors.
Symptoms of hot flashes include a sudden sensation of warmth, which are usually accompanied by skin reddening, perspiration, palpitation, anxiety, irritability, and even panic and night sweats. They can be characterized by mild warmth to profuse sweating. Typical hot flashes occur with sudden onsets of sensation of warmth in the chest, which then spreads upward to involve the neck and face. Other people feel a sudden onset of warmth all over the upper part of the body. A chill may follow a hot flash because of a subsequent drop in core temperature. Hot flashes may also be accompanied by dizziness, nausea, headaches, palpitations, and profuse sweating. Such symptoms can disrupt sleep and work and interfere with quality of life.
The severity of hot flash sensations varies greatly both from time to time in the same person and from person to person. Hot flashes have been studied in perimenopausal and postmenopausal women but have not been studied extensively in men. Hot flashes in a woman can occur several times a week to as frequently as once an hour. Each episode can last from a few seconds to sixty minutes, depending on the woman. Hot flashes are provoked by several factors such as hot weather, stress, eating, or drinking alcohol. The severity and length of hot flashes can result in sleep deprivation and interference with work and lifestyle.
Perimenopausal and postmenopausal women are likely to have hot flashes. In fact, almost 60-70% of postmenopausal women have hot flashes, and approximately 10-20% of all postmenopausal women will report intolerable symptoms. Some women may suffer from these symptoms for up to 15 years. Thus, the identification and proper management of menopausal and postmenopausal symptoms are crucial to maintaining a woman's quality of life.
Hot flashes are also a common and potentially chronic problem in men. For example, men with prostate cancer who undergo ADT may have hot flashes. This is a major quality of life issue for a significant proportion of men receiving ADT. One report shows that the natural history of hot flashes in men, including variation in severity and frequency, has not been widely studied. It is known that almost 70% of men who undergo surgical orchiectomy report hot flashes. About 70 to 80% of men on long-term androgen suppression have hot flashes, and 30 to 40% of these patients report that symptoms are a major source of discomfort.
Although the pathophysiology of hot flashes is not completely understood, it has been postulated that hot flashes result from a transient lowering of the hypothalamic temperature regulatory set point. Because of the temporal relation between changes in sexual hormone concentrations and the onset of hot flashes, it is believed that such symptoms result from declining estrogen levels or increased gonadotropin concentrations. Thus, hot flashes occur commonly in menopausal women, but also occur in premenopausal women taking anti-estrogen drugs, such as tamoxifen. Administration of aromatase inhibitors, which are anti-estrogen drugs given to menopausal women with a history of breast cancer, also can result in hot flashes as a side effect. Men on androgen deprivation treatment may also experience such symptoms.
Although estrogen replacement therapy can effectively minimize or prevent hot flashes in women, many women are concerned about potential risks of hormone replacement therapy. This is especially true for women who suffer from breast cancer or have a family history of breast cancer, and/or a history of clotting disorders.
Various non-hormonal agents for treating the symptoms of hot flashes have been tested. One of these agents is clonidine, a centrally-acting alpha2 adrenergic receptor agonist. It selectively stimulates receptors in the brain that monitor catecholamine levels in the blood. These receptors close a negative feedback loop that begins with descending sympathetic nerves from the brain that control the production of catecholamines (e.g., epinephrine, also known as adrenaline, and norepinephrine) in the adrenal medulla. By tricking the brain into believing that catecholamine levels are higher than they really are, clonidine causes the brain to reduce its signals to the adrenal medulla, leading to lower catecholamine production. The result is a lowered heart rate and blood pressure. In randomized clinical trials, clonidine was shown to be moderately more efficacious than placebo in preventing hot flashes, but adverse effects were common, including dry mouth, dizziness, and blurred vision.
There are also a number of treatments for hot flashes that appeared to have similar effects in men and women. Decreases of hot flash frequencies in women treated with clonidine are approximately 10-15 percent greater than that seen with placebo. In a double blind, cross over study of clonidine to reduce self-reported hot flash frequency in men, a similar effect was seen, but the difference from placebo effect was not statistically significant. Research has found virtually identical results for men and women receiving megestrol acetate for hot flashes, with approximately an 80% reduction in self-reported hot flash frequency compared to a 20% reduction with placebo. However, higher levels of vaginal bleeding were also associated with the use of megestrol acetate in women.
Many women seek complementary and alternative medicine (CAM) methods to ease their menopausal symptoms. Compounds used as complementary and alternative medicine include Soy Vitamin E, Red clover (Trifolium pratense), dong quai, evening primrose oil, and black cohosh (Cimicifuga racemosa).
Over the last few years, anecdotal reports suggested that antidepressants from the SSRI/SNRI groups might reduce symptoms of hot flashes. These observations led to initial pilot studies and then to randomized placebo controlled clinical trials. In pilot studies, the SNRI venlafaxine (Effexor) and the SSRI paroxetine (Paxil) were associated with hot-flash score reductions on the order of 55%-75%. Other pilot evaluations have suggested that citalopram (Celexa) and mirtazapine (Remeron) also alleviate hot flashes to a similar degree. The first reported randomized clinical trial of one of these newer antidepressants compared three doses of venlafaxine (37.5, 75, and 150 mg/day) to placebo. While low-dose venlafaxine was only mildly more effective than placebo (37% vs 27% reduction in hot-flash scores, respectively), both the moderate and high doses were associated with a statistically significant 61% reduction in hot flash scores. Fluoxetine (Prozac) 20 mg/day was associated with a 50% reduction in hot-flash scores compared to a 36% reduction with placebo. Adverse effects with SSRIs are moderate, including headache, agitation, tremor, sedation, and sexual dysfunction.
More recently, anecdotal observations suggesting efficacy led to trials to assess the value of another compound, gabapentin (Neurontin™). Gabapentin is a γ-aminobutyric acid (GABA) analog that has been most often prescribed for the treatment of seizures and naturopathic pain. It is also effective in other syndromes, such as panic disorder, social phobia, migraine headache, and essential tremor. Based on anecdotal observations, pilot and randomized trials of gabapentin for the treatment of hot flashes were launched. Results of the pilot trials suggested that gabapentin reduces the incidence of hot flashes by 42%-70%. Benefit was demonstrated regardless of the concurrent use of a stable dose of an SSRI/SNRI agent.
Serada™, another formulation of gabapentin, has also been tested in clinical trials for the treatment of menopausal hot flashes. Serada™ dosed once daily (1200 mg) or twice daily (600 mg in the morning and 1200 mg in the evening for a total of 1800 mg) resulted in a significant reduction of frequency and severity of hot flashes measured after four weeks. However, this effect was not found after 12 weeks of usage.
Given the risks of estrogen replacement therapy and marginal benefits of current non-hormonal treatments, there is a continued need for alternative methods or compositions such as drugs for treating or preventing symptoms associated with menopause, surgery, anti-estrogen drugs, and/or androgen deprivation therapy, including hot flashes. In accordance with the invention, such an alternative method and compositions are provided which avoid the dangers of estrogen replacement therapy while providing for an effective treatment of symptoms.